Ratios of specific cell types in the brain are an important substrate of the ultimate patterns of overall shape and connectivity. Control of proliferation of specific cell populations during early development must be maintained at the cellular level. I propose to use animal models to examine control of cell proliferation in the external granular layer of the cerebellum. This proliferation is affected in many experimental systems, including cerebellar mutants of the mouse and rat, embryonic and neonatal irradiation, and hypo/hyperthyroid states. The objective of this project is to examine the hypothesis that Purkinje cells are the key elements in this control system, and to examine possible mechanisms for this control. I propose to utilize two different sets of assays which have been shown to be associated with proliferation changes in the cerebellum--levels of thymidine kinase and thymidylate synthetase; and retention of embryonic patterns of glycoconjugates on the cell surface. The enzyme activities are presumably rate-limiting for DNA synthesis, and therefore directly related to cell proliferation. The cell surface changes may be part of a signalling mechanism. These properties will be tested in mice with cerebellar mutations (staggerer and Lurcher) and in mice with reversible chemically-induced cerebellar hypoplasias (due to elevated thyroid hormone and bilirubin levels), known to affect both Purkinje cells and cell proliferation. Examination of the enzyme levels and cell surface properties over this variety of experimental conditions should contribute substantially to our understanding of local signalling nechanisms for cerebellar development. Studies using primary monolayer cell cultures of the cerebellum will then be used to manipulate cell interactions and surface properties.